Novel tetracyclic imidazole derivatives: Synthesis, dynamic NMR study, and anti-inflammatory...

Novel Tetracyclic Imidazole Derivatives: Synthesis, DynamicNMR Study, and Anti-Inflammatory Evaluation

Renata Rupcic,* Marina Modric, Antun Hutinec, Ana Cikos, Barbara Stanic,

Milan Mesic, Dijana Pesic, and Mladen Mercep

GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovica 29, Zagreb HR-10000, Croatia

*E-mail: [email protected]

Received September 23, 2009

DOI 10.1002/jhet.376

Published online 3 May 2010 in Wiley InterScience (www.interscience.wiley.com).

A series of tetracyclic imidazole derivatives 9a–9v and 10a–10h are prepared by multistep route start-ing from the known tricyclic diketones 2a–2d. Intermediary dibenzooxepin[4,5-d]imidazoles (3a, 3c)and dibenzothiepin[4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formy-

lated at C(2) to afford 7a–7j. In the last steps, aldehyde group is reduced, then alkylated to the two setsof isomeric x-dimethylaminoalkyl derivatives 9a–9v. N-deprotection of 9i–9v led to the compounds10a–10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESYNMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied bydynamic NMR. Activation energies (energy barriers for interconversion) are determined to be �11.5

and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their anti-inflammatory activity.

J. Heterocyclic Chem., 47, 640 (2010).

INTRODUCTION

In our continuing efforts toward the development of

disease modifying treatments for rheumatoid arthritis

(RA), we are targeting inhibition of overproduction of

tumor necrosis factor alpha cytokine (TNF-a) that is

recognized as a key cytokine in RA progression. A

small molecule inhibitor of TNF-a would be a novel

potent anti-inflammatory drug having this distinguished

mechanism of action. In the frame of our project aimed

toward synthesis, structure determination of tetracyclic

imidazoles, and screening of their activity on the

selected biological targets, we entered the study of a

large series of dibenzo-oxepin- and dibenzo-thiepin im-

idazole derivatives. In our previous articles we have

reported on the synthesis, properties, and preliminary bi-

ological results of oxa-, aza-, and thia-dibenzoazulenes,

characterized by the annulated furane I [2], pyrrole II,

III [3], and thiophene IV, V [4] ring (Fig. 1). Prelimi-

nary results have revealed activity of these polycyclic

systems in the in vitro anti-inflammatory test in lipo-

polysaccharide (LPS) induced TNF-a production in

human peripheral blood mononuclear cells (hPBMCs)

that encouraged us to extend our effort on other five

membered heterocyclic systems [5,6].Generally, structural complexity of this specific class

of recently studied non-steroidal anti-inflammatory com-pounds increases from diaryl-substituted heterocyclesgeneral formulae VI, to polycondensed heterocyclicstructures VII. Representatives of the former are vici-naly substituted polycyclic aryl/pyridine-4-yls, potentinhibitors of p38 MAP kinase (p38) [7,8], while 2-sub-stituted-4,5-diarylimidazoles VIII are claimed as in vivoanti-inflammatory active structures (Fig. 2) [9–14].

Moreover, polycondensed heterocycles with non-aro-

matic dibenzoazulene core and annelated 5-membered het-

erocycles are repeatedly claimed as anti-inflammatory

active compounds. Among them are 2-substituted-1H-phe-nanthro[9,10-d]imidazoles IX [15], 2-substituted diben-

zo[2,3:6,7]thiepino[4,5-d]imidazoles X [16–20], 2-substi-

tuted dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles, and their

corresponding sulfoxides and sulfones XI (Fig. 3) [21].

VC 2010 HeteroCorporation

640 Vol 47

Process for preparation of 2-formylimidazole acetals

is also claimed [22], as well as 4,5-disubstituted imidaz-

ole derivatives and their use in CSBP/PK/p38 kinase

mediated diseases [13]. First synthesis of tetracyclic,

polycondensed imidazoles, presented by the formulae X,

was reported by Lombardino [17], based on the general

imidazole synthesis of Davidson et al. [23]. The same

author claimed that a wide range of polycyclic com-

pounds have anti-inflammatory and some other activities

[16,18–20]. This method has been recently improved

using microwave irradiation [24,25].

We have extended our effort to the imidazo-deriva-

tives general formulae XII, wherein an extra basic unit

was introduced at the imidazole ring to improve

physicochemical properties of this series of compounds

(Fig. 4).

RESULTS AND DISCUSSION

Chemistry. Tetracyclic imidazoles 3a–3d were pre-

pared starting from the known 11H-dibenzo[b,f]oxepin-10-ones 1a, 1c or 11H-dibenzo[b,f]thiepin-10-ones 1b,

1d, cyclic ketones characterized by activated methylene

group in the a-position to carbonyl group [16–20]. This

group was oxidized by selenium dioxide to give a-dike-tones 2a–2d. Synthesis of imidazoles 3a–3d was com-

pleted by condensation of dicarbonyl compounds 2a–2d

with paraformaldehyde and ammonium acetate in acetic

acid, according to Davidson et al., Scheme 1 [23].

N-Alkylated compounds 4a–4f were obtained from

3a, 3b using a modified method by Wolkenberg et al.[25], on treatment with sodium hydride in tetrahydrofu-

ran at 0�C followed by alkylation at elevated tempera-

tures, Scheme 2 [26].

We have used 2-trimethylsilyl-ethoxymethyl (SEM)

as effective protecting group for imidazole N(1) atom

Figure 1. Previously described oxa-, aza-, and thia-dibenzoazulenes.

Figure 2. Non-steroidal heterocyclic anti-inflammatory compounds.

Figure 3. Polycondensed heterocycles with non-aromatic dibenzoazulene core.

Figure 4. Novel tetracyclic imidazole derivatives.

May 2010 641Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,

and Anti-Inflammatory Evaluation

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

which was introduced using (2-trimethylsilyl)-ethoxy-

methyl chloride (SEMCl) [27].

In the polycondensed imidazole derivatives 3a, 3b (Y

¼ H) two tautomeric forms are equivalent and, there-

fore, single isomers 4a–4f are obtained on alkylation.

However, N(1)-alkylation of 3c, 3d affords structural

isomers 5 and 6, Scheme 3.

N-Trimethylsylil-ethoxymethylated compounds 5a, 6a

and 5b, 6b were separated by purification on silica gel

SPE cartridge using step gradient system for elution

with ethyl acetate/n-hexane. In both cases, regioisomers

5a, 6a and 5b, 6b are obtained in �1:1 ratio, revealing

minor effect of electron-withdrawing chlorine in the

meta-position of the aromatic ring. 1D NMR spectra of

compounds in the isomeric series 5 and 6 did not give

any clue on exact position of the side-chain on N(1)

atom of imidazole. Straightforward determination

required combined use of 2D NMR techniques and 1D

selective ROESY spectrum, as exemplified for the com-

pounds 5a and 6a (Fig. 5).

Correlation peaks from COSY, HMBC, HMQC, and

2D TPPI NOESY spectra afforded ambiguous informa-

tion due to the overlap of key signals, so final solution

for this problem came from the analysis of the selective

1D ROESY spectrum. Selective excitation was applied

to methylenic protons of NACH2AO unit at 5.356 and

5.372 ppm. NOE interactions were expected between

methylenic protons of NACH2AO group and ortho-pro-tons in the vicinal aromatic ring, HB for 5a and HA for

6a, which are close enough to engage in dipolar interac-

tion through space, (Fig. 6).

Protons HA and HB in both 5a and 6a have very close

chemical shifts at the applied magnetic field, and are

unequivocally assigned on the basis of their coupling

patterns. Thus, HA is coupled with ortho- and meta-pro-ton giving dd at 7.84 ppm, whereas HB is coupled only

with meta-situated proton giving doublet at 7.86 ppm.

On selective excitation of methylenic protons of

NACH2AO unit in 6a doublet of HB proton disap-

peared, while resonance lines for proton HA remained,

revealing its vicinity to the methylenic group, and thus

syn (cis) orientation of the side chain on N(1) of imidaz-

ole ring to the aromatic ring that has no chlorine in

meta-position to the annulated heterocycle.

Scheme 1

Scheme 2

Scheme 3

642 Vol 47R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep


Having this result in hands, ulterior synthetic steps

have been performed on the separated isomers with

known structure. From 4, 5, and 6 are obtained C(2) for-

mylated derivatives 7 on generation of carbanion at C(2)

of imidazole ring by n-butyllithium/tetrahydrofuran at

�78�C, followed by treatment with DMF at r.t., Scheme

4 [9,28].

Reduction of 7a–7h with sodium borohydride at r.t.

afforded benzylic alcohols 8a–8h. From 7i and 7j under

the same conditions are obtained 8i and 8j. Both sets of

hydroxymethyl imidazole derivatives are converted to

dialkylaminoalkyl ethers 9a–9v on treatment with x-chloroalkyl-dimethylamines under phase transfer condi-

tions in the presence of benzyltriethylammonium chlo-

ride (BTEAC), Scheme 5 [4,29].

Products 10a–10h are obtained on cleavage of 2-(tri-

methylsilyl)ethoxymethyl group with 0.5M hydrochloric

acid/methanol, Scheme 6 [9].

Conformational properties of representative oxepin

(8a) and thiepin (8b) tetracycles. Conformational mo-

bility and preferred conformation in solution of the 7-

membered ring play an important role in biological ac-

tivity of non-aromatic polycyclic compounds. Illustrative

example represents octoclothepin 14 (Fig. 7), centrochi-

ral, and planar-chiral compound with dibenzo-thiepine

tricyclic core, wherein two conformers with inversed 7-

membered ring are diastereotopic. An early study of (S)-14 (Fig. 7), neuroleptic compound that binds on dopa-

mine D-2 receptor [30], has revealed that stable confor-

mation of (S)-14, which is responsible for the dopamine

D-2 receptor antagonism, is significantly different from

the one observed in the crystal [31].

On the other hand, conformational mobility of diben-

zothiepines with sulfide 1b and sulfoxide 15 unit in the

bridge, was studied by dynamic NMR [32]. Huge differ-

ence in the activation energies for ring-inversion was

observed; 9.3 kcal/mol for 1b and 23 kcal/mol for 15,

revealing that at ambient temperature only the later may

be separated into stable conformers (Fig. 8).

For many condensed non-aromatic heterocycles with

one heteroatom in the 7-membered ring correlation

between conformational properties and biological activ-

ities are studied. Detailed study of N-acylbenzazepineswith interesting pharmacological properties [33], by

dynamic NMR is an instructive case [34–36]. For dihy-

drobenz/b/azepines thermodynamic parameters for con-

formation equilibria are determined by dynamic NMR

[37,38].

In view of the importance of conformational mobility

of non-aromatic polycondensed heterocycles, we have

determined difference in conformational mobility of the

two representatives of oxepines and thiepines, com-

pounds 8a and 8b, respectively. They are selected due

Figure 5. Regioisomeres determined by 2D NMR techniques and 1D

selective ROESY spectrum.

Figure 6. Comparison between aromatic region of 1H (a) and 1D selective ROESY (b) spectra of 6a.




to their well resolved peaks for methylenic protons HA,

HB, present in the 5-member chelate ring

C(2)ACHAHBAOAH��N(3) formed by hydrogen bond

to N(3) atom, formulae 8a, 8b (Fig. 9).

On the basis of the reported results, we expected no-

table difference of the energy for conformational inver-

sion for these two compounds. To our satisfaction,

dynamic NMR study has revealed two different temper-

ature intervals for the collapse of the AB(X) system into

A2 system of the methylenic protons. Series of proton

NMR spectra acquired in temperature range where the

coalescence of proton signals occurs are shown in the

Figures 10 and 11.

Activation energies (energy barriers for interconver-

sion) for compounds 8a and 8b are determined and

results are presented in Table 1.

Biology. Among many discovered biological targets

in the past 30 years, TNF-a, interleukin 1 (IL-1), p38,

and COX-2 enzyme belong to the group of the most

studied and the most relevant mediators of

Scheme 4

Scheme 5

inflammation [39]. Overproduction inhibition of these

cytokines which are responsible for inflammation has

been proposed as a disease modifying approach

towards the treatment of inflammatory disorders. The

over-expression of TNF-a cytokine has been impli-

cated in a number of serious inflammatory disorders.

Consequently, agents that inhibit the production of

TNF-a can decrease levels of inflammatory response,

and thereby reduce inflammation and prevent further

tissue destruction.

From medicinal chemistry point of view, connecting

previous knowledge about anti-inflammatory properties

of some compounds with today’s understanding of im-

portant key players in inflammation mechanism could

provide rational approach to the lead molecules that

may be further optimized for better activity and

Scheme 6

Figure 7. Octoclothepin and its (S)-conformer.

Figure 8. Dibenzothiepines with sulfide and sulfoxide unit in the

bridge.

Figure 9. Methylenic protons HA and HB in the 5-membered chelate

ring.




selectivity profile and desirable pharmacokinetic proper-

ties. Along this line we have continued our project of

the synthesis of tetracyclic target structures and their

testing on inhibition of LPS stimulated TNF-a produc-

tion. In vitro biological tests are performed on some

intermediates and all tetracyclic compounds 9 and 10 to

test their ability to inhibit TNF-a production in LPS-

activated hPBMC assay [5,6].

Compounds possessing alkoxymethylene linker (ether)

at position C(2) on imidazole ring showed potency to in-

hibit TNF-a production in vitro in low micromolar

range with IC50 values for the most potent compounds

in the range of 1–3 lM.

According to obtained results dibenzo-oxepin- and

dibenzo-thiepin imidazole derivatives were recognized

as a novel class of tetracyclic compounds with anti-

inflammatory activity through specific inhibition of

TNF-a secretion.

EXPERIMENTAL

Chemistry. Commercial reagents were used as received

without additional purification. All used chemicals and sol-vents were p.a. purity. Differential scanning calorimetry datawere collected on a Mettler Toledo differential scanning calo-rimeter 822e/500 using Mettler Toledo STARe software. Sam-ples about 5 mg were weighed into Al-pans (40 lL) with

pierced cover. Dry nitrogen was used as purge gas (purge: 50mL/min). The heating rate of 10�C/min over the range 25–300�C was used. The instrument was calibrated using certifiedindium and zinc. IR spectra were recorded as potassium bro-

mide (KBr) pastilles or as a film on a sodium chloride plate,on a Nicolet Magna IR 760 FT IR-spectrophotometer, and ona Bruker Vertex 70 as ATR (ZnSe) powder or film cast fromDCM solution. One- and two-dimensional NMR spectra wererecorded on Bruker Avance DPX 300 (300 MHz), Bruker

Avance DRX 500 (500 MHz), and Bruker Avance III 600(600 MHz) spectrometers. Deuterated dimethylsulfoxide(DMSO-d6) and deuterated chloroform (CDCl3) were used assolvents and tetramethylsilan (TMS) as an internal standard.Purity of the compounds was obtained on a Waters HPLC-UV/

MS Autopurification System with a Micromass ZQ and aWaters 996 Photodiode Array Detector, and on Varian Chrom-pack CP-3800 Gas Chromatograph with a Varian ChrompackSaturn 2000 MS/MS detector. HRMS data were acquired usingQ-TOF 2 Waters system. Thin layer chromatography (TLC)

was run on Merck Silica gel 60 F254 plates, spots detectedwith UV light at 254 and/or 365 nm. Proportions of solventsused for TLC are by volume.

Products were purified using Solid Phase Extraction (SPE)

columns on an automated SPE purification system (FlashMas-ter II).

Figure 10. 1H NMR spectra of 8a acquired in acetone-d6 in the tem-

perature intervals from 25�C to �60�C (coalescence range for the HA

and HB protons signals).

Figure 11. 1H NMR spectra of 8b acquired in DMSO-d6 in the tem-

perature intervals from 25�C to 60�C (coalescence range for the HA

and HB protons signals).

Table 1

Activation energies for compounds 8a and 8b.

Compound 8a 8b

Solvent Acetone-d6 DMSO-d6Starting temperature (�C) 25 25

Ending temperature (�C) �60 80

Coalescence temperature TC (�C) �40 50

Separation between signals Dm (Hz) 17.3 4.9

Coupling constant 2JA,B (Hz) 13.1 13.1

Rate constant at the

coalescence temperature kC (Hz)

80.9 72.1

Gibbs energy DGCz (kcal/mol) 11.5 16.2

zActivated complex, transition state.



General procedure for reaction of ketones 1 with sele-

nium dioxide (preparation of compounds 2). To the suspen-sion of selenium dioxide (1.74 g, 15.70 mmol) in glacial acetic

acid (10 mL) was added a solution of ketone 1 (14.3 mmol) inglacial acetic acid (30 mL). The suspension was heated for 2 hat 100�C and undissolved material filtered off. The filtrate wasdiluted with water (50 mL) and extracted with dichlorome-thane (2 � 50 mL). Organic extracts were washed with water

(3 � 50 mL), and saturated sodium hydrogencarbonate (3 �50 mL), dried over anhydrous sodium sulfate, concentrated,and then precipitated from n-hexane/dichloromethane to givecompound 2.

Dibenzo[b,f]oxepin-10,11-dione (2a). Obtained from 1a as

a yellow solid: Yield 85%; mp 116.68�C; IR (KBr): 1670,1600, 1469, 1447, 1281, 1220, 926, 771 cm�1; 1H NMR (500MHz, CDCl3): d 7.35 (td, J ¼ 7.55, 1.07 Hz, 2H), 7.42–7.43(m, 1H), 7.43–7.45 (m, 1H), 7.64–7.68 (m, 2H), 7.99 (d, J ¼1.83 Hz, 1H), 8.00 ppm (d, J ¼ 1.83 Hz, 1H); 13C NMR (126

MHz, CDCl3): d 121.60, 125.50, 126.11, 131.71, 135.83,156.65, 186.31 ppm; MS: m/z 225.00 [MþH]þ.

Dibenzo[b,f]thiepin-10,11-dione (2b). Obtained from 1b asa yellow solid: Yield 80%; mp 122.69�C; IR (KBr): 1675,

1581, 1435, 1280, 1258, 1219, 916, 760 cm�1; 1H NMR (500MHz, CDCl3): d 7.31–7.37 (m, 4H), 7.51 (dd, J ¼ 7.63, 1.53Hz, 2H), 7.69 ppm (dd, J ¼ 7.17, 1.98 Hz, 2H); 13C NMR (75MHz, CDCl3): d 129.23, 131.26, 132.09, 132.98, 134.55,139.35, 190.62 ppm; MS: m/z 240.09 [MþH]þ.

2-Chlorodibenzo[b,f]oxepin-10,11-dione (2c). Obtainedfrom 1c as a yellow solid: Yield 74%; mp 103.23�C; IR(KBr): 1691, 1673, 1599, 1467, 1449, 1402, 1290, 1266, 1224,1118, 842, 765 cm�1; 1H NMR (500 MHz, CDCl3): d 7.35–7.44 (m, 3H), 7.60 (dd, J ¼ 8.70, 2.59 Hz, 1H), 7.65–7.70 (m,

1H), 7.95–8.01 ppm (m, 2H); 13C NMR (126 MHz, CDCl3): d156.42, 136.01, 135.74, 131.87, 131.10, 130.89, 125.87,123.36, 121.52 ppm; MS: m/z 259.1 [MþH]þ.

2-Chlorodibenzo[b,f]thiepin-10,11-dione (2d). Obtainedfrom 1d as a yellow solid: Yield 79%; mp 167.94�C; IR

(KBr): 1689, 1583, 1274, 1213, 1094, 829, 761 cm�1; 1HNMR (500 MHz, CDCl3): d 7.40–7.52 (m, 3H), 7.56–7.65 (m,2H), 7.77 (d, J ¼ 2.14 Hz, 1H), 7.80 ppm (dd, J ¼ 7.02, 1.83Hz, 1H); 13C NMR (126 MHz, CDCl3): d 129.78, 131.25,131.65, 132.44, 133.08, 133.21, 133.41, 133.73, 134.21,

135.92, 139.49, 140.76, 189.21, 189.83 ppm; MS: m/z 275.0[MþH]þ.

General procedure for reaction of diketones 2 with para-

formaldehyde (preparation of compounds 3). A suspension

of compound 2 (5.35 mmol), ammonium acetate (4.13 g, 53.5mmol), and paraformaldehyde (0.19 g, 5.0 mmol) in glacialacetic acid (32 mL) was heated to reflux. After 2 h, reactionmixture was cooled, diluted with water (100 mL), andextracted with ethyl acetate (2 � 50 mL). Organic extracts

were washed with water (3 � 100 mL), saturated sodiumhydrogencarbonate (3 � 100 mL), and brine (100 mL), driedover anhydrous sodium sulfate, concentrated, and then purifiedon silica gel SPE cartridge using step gradient system for elu-tion dichloromethane/(dichloromethane/methanol/ammonium

hydroxide 90:9:1.5) to give compound 3.1H-Dibenzo[2,3:6,7]oxepino[4,5-d]imidazole (3a). Obtained

from 2a as a white solid: Yield 81%; mp 234.05�C; IR (KBr):3286, 2941, 2871, 1730, 1165, 1096, 856 cm�1; 1H NMR (500MHz, DMSO-d6): d 7.27 (d, J ¼ 4.88 Hz, 2H), 7.32 (br. s.,

2H), 7.37 (br. s., 2H), 7.55 (d, J ¼ 7.02 Hz, 1H), 7.76 (d, J ¼6.71 Hz, 1H), 7.96 (s, 1H), 12.92 ppm (br. s., 1H); 13C NMR(126 MHz, DMSO-d6): d 121.48, 122.63, 126.44, 127.08,127.36, 132.06, 136.66, 155.30 ppm; HRMS: m/z calcd. forC15H11N2O: 235.0871 [MþH]þ, found 235.0865.

1H-Dibenzo[2,3:6,7]thiepino[4,5-d]imidazole (3b). Obtainedfrom 2b as a yellow solid: Yield 75%; mp 263.23�C; IR(KBr): 2815, 2641, 1511, 1478, 953, 758, 651 cm�1; 1H NMR(500 MHz, DMSO-d6): d 7.37 (t, J ¼ 7.17 Hz, 2H), 7.44 (t, J¼ 7.32 Hz, 2H), 7.59 (br. s., 3H), 7.81 (br. s., 1H), 7.99 (s,

1H), 12.92 ppm (br. s., 1H); 13C NMR (75 MHz, DMSO-d6):d 136.85, 133.60, 132.60, 132.17, 131.63, 130.90, 128.75,128.35, 127.65, 126.85 ppm; HRMS: m/z calcd. forC15H11N2S: 251.0638 [MþH]þ, found 251.0630.

11-Chloro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazole(3c). Obtained from 2c as a beige amorphous solid: Yield84%; IR (KBr): 3113, 14785, 953, 758, 651 cm�1; 1H NMR(600 MHz, DMSO-d6): d 7.29 (dt, J ¼ 7.76, 3.97 Hz, 1H),7.33–7.45 (m, 4H), 7.66 (br. s., 2H), 8.00 (s, 1H), 13.00 ppm

(br. s., 1H), 13C NMR (151 MHz, DMSO-d6): d 153.81,152.60, 137.92, 129.36, 125.58, 123.37 ppm; HRMS: m/zcalcd. for C15H10ClN2O: 269.0482 [MþH]þ, found 269.0468.

11-Chloro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazole(3d). Obtained from 2d as a yellow solid: Yield 68%; mp

241.28�C; IR (KBr): 2806, 2639, 1475, 768, 649 cm�1; 1HNMR (500 MHz, DMSO-d6): d 7.33–7.53 (m, 3H), 7.53–7.67(m, 3H), 7.78 (br. s., 1H), 8.04 (s, 1H), 13.03 ppm (d, J ¼13.73 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d 127.23,127.48, 128.26, 129.55, 129.72, 130.00, 130.85, 131.02,

133.23, 133.31, 133.79, 133.97, 135.90, 137.76, 138.30 ppm;HRMS: m/z calcd. for C15H10ClN2S: 285.0253 [MþH]þ, found285.0245.

General procedures for N-alkylation of the compounds 3

(preparation of compounds 4). N-Methylation. To a solu-

tion of 3 (0.5 g, 2.13 mmol) in dry tetrahydrofuran (23 mL)the 60% suspension of NaH in mineral oil (0.26 g, 6.4 mmol)was added under stirring at 0�C. The reaction mixture wasstirred for 30 min at 0�C, then MeI (0.13 mL, 2.13 mmol) was

added and reaction mixture was stirred at room temperaturefor 2 h. Then it was concentrated, diluted with water (100mL), and extracted with dichloromethane (3 � 50 mL). Theorganic extract was washed with brine (100 mL), dried overanhydrous sodium sulfate, and evaporated. After purification

on silica gel SPE cartridge using step gradient system for elu-tion dichloromethane/(dichloromethane/methanol/ammoniumhydroxide 90:5:0.5) N-methylated compounds 4a and 4b wereisolated.

1-Methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazole(4a). Obtained from 3a as a yellowish solid: Yield 73%; mp138.05�C; IR (KBr): 1514, 1444, 1248, 1201, 810, 765, 733cm�1; 1H NMR (500 MHz, DMSO-d6): d 3.91 (s, 3H), 7.26(ddd, J ¼ 7.55, 6.49, 2.14 Hz, 1H), 7.29–7.38 (m, 3H), 7.39–7.44 (m, 1H), 7.45–7.48 (m, 1H), 7.66 (dd, J ¼ 7.63, 1.53 Hz,

1H), 7.71–7.74 (m, 1H), 7.94 ppm (s, 1H); 13C NMR (126MHz, DMSO-d6): d 33.62, 121.47, 122.63, 123.27, 125.78,125.85, 126.65, 126.72, 126.83, 128.20, 129.20, 129.65,137.54, 141.60, 155.79, 155.89 ppm; HRMS: m/z calcd. for

C16H13N2O: 249.1028 [MþH]þ, found 249.1019.1-Methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazole

(4b). Obtained from 3b as a yellowish solid: Yield 94%; mp137.12�C; IR (KBr): 3051, 2922, 1510, 1467, 773, 758, 741,




643 cm�1; 1H NMR (500 MHz, DMSO-d6): d 3.83 (s, 3H),7.33–7.37 (m, 1H), 7.40–7.50 (m, 3H), 7.57 (dd, J ¼ 7.63,1.22 Hz, 1H), 7.64 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.70 (dd, J ¼7.48, 1.37 Hz, 1H), 7.78 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.97ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 33.49,

128.23, 128.37, 128.78, 129.15, 129.26, 130.57, 132.50,133.16, 133.84, 134.16, 138.41, 140.73, 141.29 ppm; HRMS:m/z calcd. for C16H13N2S: 265.0799 [MþH]þ, found 265.0791.

N-Phenylethylation. To a solution of 3 (0.2 g, 0.85 mmol)in dry tetrahydrofuran (7 mL) the 60% suspension of sodium

hydride in mineral oil (0.10 g, 2.56 mmol) was added understirring at 0�C. The reaction mixture was stirred for 30 min at0�C, then 2-phenylethyl bromide (0.17 mL, 1.28 mmol) wasadded and reaction mixture was heated under stirring andreflux. After 2 h, another portion of the 60% suspension of so-

dium hydride in mineral oil (0.03 g, 0.85 mmol) and 2-phenyl-ethyl bromide (0.12 mL, 0.85 mmol) were added and stirringunder reflux was continued. After 1 day, another portion of the60% suspension of sodium hydride in mineral oil (0.03 g, 0.85

mmol) and 2-phenylethyl bromide (0.12 mL, 0.85 mmol) wereadded and stirring under reflux was continued for 1 day. Thenit was cooled to room temperature, concentrated, and dilutedwith water (50 mL) and extracted with dichloromethane (3 �30 mL). The organic extract was washed with brine (50 mL),

dried over anhydrous sodium sulfate, and evaporated. After pu-rification on silica gel SPE cartridge using step gradient systemfor elution n-hexane/ethyl acetate N-phenylethylated com-pounds 4c and 4d were isolated.

1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imid-azole (4c). Obtained from 3a as a yellowish amorphous solid:Yield 64%; IR (KBr): 1509, 1443, 1201, 1079, 809, 762, 741,696 cm�1; 1H NMR (500 MHz, DMSO-d6): d 3.02 (t, J ¼7.48 Hz, 2H), 4.55 (t, J ¼ 7.48 Hz, 2H), 7.13–7.17 (m, 2H),7.17–7.22 (m, 1H), 7.23–7.28 (m, 3H), 7.30–7.39 (m, 3H),

7.40–7.45 (m, 1H), 7.46–7.49 (m, 1H), 7.64–7.72 (m, 2H),7.89 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 36.10,47.44, 121.43, 122.69, 123.49, 125.75, 126.02, 126.07, 126.31,126.82, 126.95, 128.13, 128.80, 128.99, 129.26, 129.72,

137.93, 138.02, 141.15, 155.81, 156.10 ppm; HRMS: m/zcalcd. for C23H19N2O: 339.1497 [MþH]þ, found 339.1496.

1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imid-azole (4d). Obtained from 3b as a white solid: Yield 79%; mp156.93�C; IR (KBr): 3049, 3022, 2939, 1505, 756, 740, 658

cm�1; 1H NMR (500 MHz, DMSO-d6): d 2.79–2.95 (m, 2H),4.36–4.45 (m, 1H), 4.58 (ddd, J ¼ 13.73, 7.78, 5.34 Hz, 1H),7.05–7.09 (m, 2H), 7.14–7.24 (m, 3H), 7.32–7.37 (m, 1H),7.39–7.45 (m, 2H), 7.48 (td, J ¼ 7.55, 1.37 Hz, 1H), 7.58 (dd,J ¼ 7.63, 1.22 Hz, 1H), 7.64 (dd, J ¼ 7.63, 1.53 Hz, 1H),

7.71 (dd, J ¼ 7.63, 1.53 Hz, 1H), 7.75 (dd, J ¼ 7.93, 1.53 Hz,1H), 7.85 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d36.15, 47.36, 126.86, 127.97, 128.30, 128.73, 128.78, 128.99,129.13, 129.31, 129.84, 132.50, 132.84, 133.59, 133.87,134.39, 137.96, 138.32, 140.28, 141.84 ppm; HRMS: m/zcalcd. for C23H19N2S: 355.1269 [MþH]þ, found 355.1273.

N-Trimethylsylil-ethoxymethylation. To a solution of 3 (0.5g, 2.13 mmol) in dry tetrahydrofuran (23 mL) the 60% suspen-sion of sodium hydride in mineral oil (0.26 g, 6.40 mmol) was

added under stirring at 0�C. The reaction mixture was stirredfor 30 min at 0�C, then 2-(trimethylsilyl)ethoxymethyl chloride(0.38 mL, 2.13 mmol) was added and reaction mixture wasstirred at room temperature for 2 h. Then it was concentrated,

diluted with water (100 mL), and extracted with dichlorome-thane (3 � 50 mL). The organic extract was washed with brine(100 mL), dried over anhydrous sodium sulfate, and evapo-rated. After purification on silica gel SPE cartridge using stepgradient system for elution ethyl acetate/n-hexane N-trimethyl-

sylil-ethoxymethylated compounds 4e and 4f were isolated.1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]oxe-

pino[4,5-d]imidazole (4e). Obtained from 3a as a yellowishsolid: Yield 60%; mp 98.50�C; IR (KBr): 1513, 1250, 1244,1080, 838, 766 cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00

(s, 9H), 0.93–0.98 (m, 2H), 3.68–3.73 (m, 2H), 5.57 (s, 2H),7.29–7.36 (m, 2H), 7.39–7.42 (m, 2H), 7.44–7.52 (m, 2H),7.78 (ddd, J ¼ 7.48, 1.22, 1.07 Hz, 1H), 7.91 (dd, J ¼ 7.93,1.53 Hz, 1H), 8.22 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d �1.03, 17.58, 65.96, 74.46, 121.50, 122.66, 123.16,

125.83, 125.98, 126.76, 126.94, 127.14, 127.92, 129.52,130.04, 137.99, 141.99, 156.01, 156.09 ppm; HRMS: m/zcalcd. for C21H25N2O2Si: 365.1685 [MþH]þ, found 365.1660.

1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]-thiepino[4,5-d]imidazole (4f). Obtained from 3b as a yellowishsolid: Yield 79%; mp 104.47�C; IR (KBr): 2955, 1504, 1248,1083, 863, 835, 776, 763 cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.85–0.97 (m, 2H), 3.55 (td, J ¼ 9.54,6.56 Hz, 1H), 3.69 (td, J ¼ 9.46, 6.71 Hz, 1H), 5.46 (d, J ¼11.29 Hz, 1H), 5.66 (d, 1H), 7.41–7.46 (m, 1H), 7.47–7.55 (m,3H), 7.64 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.75–7.79 (m, 1H),7.85 (dd, J ¼ 7.93, 1.22 Hz, 2H), 8.27 ppm (s, 1H); 13C NMR(126 MHz, DMSO-d6): d �1.07, 17.61, 66.02, 74.52, 128.46,128.70, 129.06, 129.20, 129.27, 129.61, 130.49, 132.51,

132.61, 133.45, 133.90, 134.50, 138.08, 141.16, 141.69 ppm;HRMS: m/z calcd. for C21H25N2OSSi: 381.1451 [MþH]þ,found 381.1436.

General procedure for N-trimethylsylil-ethoxymethyla-

tion of the compounds 3 (preparation of structural isomers

5 and 6). To a solution of 3 (1.0 g, 3.72 mmol) in dry tetrahy-drofuran (30 mL) the 60% suspension of sodium hydride inmineral oil (0.45 g, 11.20 mmol) was added under stirring at0�C. The reaction mixture was stirred for 30 min at 0�C, then2-(trimethylsilyl)ethoxymethyl chloride (0.66 mL, 3.72 mmol)was added and reaction mixture was stirred at room tempera-ture for 2 h. Then it was concentrated, diluted with water (30mL), and extracted with dichloromethane (3 � 25 mL). Theorganic extract was washed with brine (50 mL), dried over an-

hydrous sodium sulfate, and evaporated. After purification onsilica gel SPE cartridge using step gradient system for elutionethyl acetate/n-hexane structural isomers 5 and 6 wereisolated.

11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazole (5a). Obtained from 3c as ayellowish solid: Yield 31%; mp 84.67�C; IR (KBr): 3093, 2957,1515, 1245, 1200, 1077, 833, 768 cm�1; 1H NMR (500 MHz,DMSO-d6): d 0.00 (s, 9H), 0.96 (t, J ¼ 7.9 Hz, 2H), 3.72 (t, J ¼8.0 Hz, 2H), 5.56 (s, 2H), 7.32 (m, 1H), 7.41 (m, 2H), 7.51 (m,

2H), 7.77 (d, J ¼ 7.0 Hz, 1H), 7.96 (d, J ¼ 1.8 Hz, 1H), 8.25ppm (s, 1H) 13C NMR (126 MHz, DMSO-d6): d�1.04, 17.58,66.04, 74.55, 122.69, 122.80, 123.46, 126.04, 126.28, 127.27,127.47, 129.07, 129.74, 129.94, 130.37, 136.67, 142.32, 154.50,

155.78 ppm ; HRMS: m/z calcd. for C21H24N2O2SiCl: 399.1296[MþH]þ, found 399.1281.

11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]thiepino[4,5-d]imidazole (5b). Obtained from 3d as



a yellowish solid: Yield 33%; mp 117.74�C; IR (KBr): 2976,2940, 1738, 1621, 1456, 1381, 1169, 1074, 1014, 732 cm�1;1H NMR (600 MHz, DMSO-d6): d 0.00 (m, 9H), 0.932 (m,2H), 3.60 (td, J ¼ 9.7, 6.4 Hz, 1H), 3.71 (td, J ¼ 9.7, 6.5 Hz,1H), 5.41 (d, J ¼ 11.3 Hz, 1H), 5.63 (d, J ¼ 11.3 Hz, 1H),

7.43 (ddd, J ¼ 7.6, 7.5, 1.5 Hz, 1H), 7.50 (td, J ¼ 7.5, 1.3 Hz,1H), 7.53 (dd, J ¼ 8.3, 2.4 Hz, 1H), 7.62 (dd, J ¼ 7.8, 1.0 Hz,1H), 7.74 (d, J ¼ 8.4 Hz, 1H), 7.83 (dd, J ¼ 7.7, 1.2 Hz, 1H),7.95 (d, J ¼ 2.3 Hz, 1H), 8.28 ppm (s, 1H); 13C NMR (151MHz, DMSO-d6): d �0.01, 18.67, 67.04, 75.52, 129.00,

129.61, 130.20, 130.28, 130.38, 130.43, 133.55, 134.00,134.08, 135.18, 135.36, 136.37, 138.88, 142.55, 143.45 ppm ;HRMS: m/z calcd. for C21H24N2OSClSi: 415.1067 [MþH]þ,found 415.1067.

5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazole (6a). Obtained from 3c as

a yellowish solid: Yield 47%; mp 93.25�C; IR (KBr): 2950,

1514, 1246, 1094, 1074, 834, 811 cm�1; 1H NMR (500 MHz,

DMSO-d6): d 0.00 (m, 9H), 0.96 (t, J ¼ 7.9 Hz, 2H), 3.72 (t,

J ¼ 8.0 Hz, 2H), 5.56 (s, 2H), 7.32 (m, 1H), 7.41 (m, 2H),

7.51 (m, 2H), 7.77 (d, J ¼ 7.0 Hz, 1H), 7.96 (d, J ¼ 1.8 Hz,

1H), 8.25 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d�0.98, 17.57, 66.03, 74.42, 121.50, 124.37, 124.95, 125.53,

126.11, 126.45, 127.06, 127.56, 129.53, 129.86, 130.17,

138.80, 142.44, 154.55, 155.76 ppm ; HRMS: m/z calcd. for

C21H24N2O2SiCl: 399.1296 [MþH]þ, found 399.1289.

5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]thiepino[4,5-d]imidazole (6b). Obtained from 3d as

a yellowish solid: Yield 49%; mp 113.80�C; IR (KBr): 3098,2950, 1583, 1505, 1407, 1330, 1263, 1249, 1091, 1083, 1071,1019, 859, 838, 810, 767, 638 cm�1; 1H NMR (600 MHz,DMSO-d6): d 0.00 (s, 9H), 0.91 (m, 2H), 3.55 (td, J ¼ 9.6, 6.7Hz, 1H), 3.69 (td, J ¼ 9.5, 6.8 Hz, 1H), 5.48 (d, J ¼ 11.3 Hz,

1H), 5.67 (d, J ¼ 11.3 Hz, 1H), 7.50 (dd, J ¼ 8.4, 2.4 Hz,1H), 7.53 (m, 1H), 7.55 (m, 1H), 7.66 (d, J ¼ 8.4 Hz, 1H),7.77 (m, 1H), 7.81 (d, J ¼ 2.4 Hz, 1H), 7.87 (m, 1H), 8.31ppm (s, 1H); 13C NMR (151 MHz, DMSO-d6): d 0.00, 18.67,

67.16, 75.69, 128.73, 129.81, 129.88, 130.62, 130.99, 132.24,133.21, 133.45, 134.96, 135.04, 135.08, 135.22, 140.88,141.49, 142.55 ppm; HRMS: m/z calcd. for C21H24N2OSClSi:415.1067 [MþH]þ, found 415.1053.

General procedure for C(2) formylation of the com-

pounds 4, 5, and 6 (preparation of compounds 7). To a so-lution of 4 (0.44 g, 1.77 mmol) in dry tetrahydrofuran (8 mL)1.6M solution of n-butyllithium in n-hexane (1.22 mL, 1.95mmol) was added under stirring at �78�C. The reaction mix-ture was stirred for 15 min at �78�C, then dry DMF (0.17

mL, 2.13 mmol) was added and reaction mixture was stirred atroom temperature for 1 h. Then it was diluted with water (50mL) and extracted with dichloromethane (3 � 30 mL). The or-ganic extract was washed with brine (50 mL), dried over anhy-drous sodium sulfate, evaporated, and then purified on silica

gel SPE cartridge using step gradient system for elution n-hex-ane/dichloromethane to give compound 7.

1-Methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazole-2-car-baldehyde (7a). Obtained from 4a as a yellow solid: Yield

74%; mp 161.69�C; IR (ATR): 2921, 2849, 1681, 1511, 1445,1209, 800, 768, 745 cm�1; 1H NMR (500 MHz, DMSO-d6): d4.17 (s, 3H), 7.31–7.41 (m, 2H), 7.44–7.46 (m, 2H), 7.55–7.57(m, 2H), 7.74–7.80 (m, 1H), 7.83 (d, J ¼ 7.63 Hz, 1H), 9.88ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 34.48,

121.44, 121.73, 122.96, 126.13, 126.21, 126.75, 127.16,128.33, 130.46, 131.64, 133.19, 139.34, 144.74, 156.88,157.26, 182.69 ppm; HRMS: m/z calcd. for C17H13N2O2:277.0977 [MþH]þ, found 277.0963.

1-Methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazole-2-car-baldehyde (7b). Obtained from 4b as a yellow solid: Yield52%; mp 215.10�C; IR (ATR): 2918, 2835, 1682, 1443, 825,760 cm�1; 1H NMR (500 MHz, DMSO-d6): d 4.08 (s, 3H),7.41–7.52 (m, 2H), 7.52–7.57 (m, 2H), 7.65 (dd, J ¼ 7.78,1.37 Hz, 1H), 7.71–7.80 (m, 2H), 7.87 (dd, J ¼ 7.78, 1.68 Hz,

1H), 9.92 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d34.46, 128.63, 129.39, 129.58, 129.72, 129.85, 130.80, 130.89,132.78, 134.26, 134.30, 135.74, 136.40, 137.03, 142.85,143.76, 182.99 ppm; HRMS: m/z calcd. for C17H13N2OS:293.0749 [MþH]þ, found 293.0740.

1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidaz-ole-2-carbaldehyde (7c). Obtained from 4c as a yellowish solid:

Yield 70%; mp 157.69�C; IR (ATR): 3062, 3025, 2821, 1674,

1508, 1449, 1421, 1202, 770, 743 cm�1; 1H NMR (500 MHz,

DMSO-d6): d 3.03 (t, J ¼ 7.32 Hz, 2H), 4.90 (t, J ¼ 7.48 Hz, 2H),

7.07–7.11 (m, 2H), 7.15–7.24 (m, 3H), 7.33 (ddd, J ¼ 7.55, 6.03,

2.59 Hz, 1H), 7.38–7.49 (m, 3H), 7.49–7.57 (m, 2H), 7.75–7.82 (m,

2H), 9.82 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 36.41,

47.23, 121.64, 123.02, 126.17, 126.31, 126.72, 127.06, 127.29,

127.72, 128.79, 128.88, 130.51, 131.65, 132.70, 137.41, 139.83,

144.54, 157.18, 157.57 ppm, 182.55; HRMS: m/z calcd. for

C24H19N2O2: 367.1447 [MþH]þ, found 367.1454.1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imid-

azole-2-carbaldehyde (7d). Obtained from 4d as a yellowishsolid: Yield 52%; mp 193.04�C; IR (ATR): 1684, 1421, 827,748, 696 cm�1; 1H NMR (500 MHz, DMSO-d6): d 2.80–2.95

(m, 2H), 4.74 (dt, J ¼ 14.04, 7.02 Hz, 1H), 5.04 (dt, J ¼14.11, 7.13 Hz, 1H), 6.95–6.99 (m, 2H), 7.12–7.17 (m, 3H),7.42 (td, J ¼ 7.55, 1.68 Hz, 1H), 7.46–7.57 (m, 3H), 7.62 (dd,J ¼ 7.63, 1.22 Hz, 1H), 7.72–7.77 (m, 2H), 7.83 (dd, J ¼7.48, 1.68 Hz, 1H), 9.81 ppm (s, 1H); 13C NMR (126 MHz,

DMSO-d6): d 36.48, 46.88, 126.91, 128.68, 128.72, 128.89,129.29, 129.51, 129.71, 130.69, 131.12, 132.71, 132.77,134.26, 134.90, 136.03, 136.38, 136.97, 137.30, 143.46,182.82 ppm; HRMS: m/z calcd. for C24H19N2OS: 383.1218[MþH]þ, found 383.1229.

1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]oxe-pino[4,5-d]imidazole-2-carbaldehyde (7e). Obtained from 4e as awhite solid: Yield 78%; mp 83.24�C; IR (ATR): 952, 1686,1507, 1450, 1430, 1240, 1211, 1082, 856, 832, 801, 762, 691

cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.93–0.98 (m, 2H), 3.73–3.79 (m, 2H), 5.93 (s, 2H), 7.36–7.46 (m,2H), 7.49–7.57 (m, 2H), 7.57–7.65 (m, 2H), 7.87–7.96 (m,1H), 7.96–8.04 (m, 1H), 9.97 ppm (s, 1H); 13C NMR (126MHz, DMSO-d6): d �1.07, 17.71, 66.45, 73.60, 121.51,

121.71, 123.04, 126.26, 126.35, 126.51, 127.35, 128.47,130.72, 132.01, 133.32, 139.67, 144.69, 157.02, 157.56,182.76 ppm; HRMS: m/z calcd. for C22H25N2O3Si: 393.1634[MþH]þ, found 393.1631.

1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]-thiepino[4,5-d]imidazole-2-carbaldehyde (7f). Obtained from4f as a yellowish solid: Yield 74%; mp 82.94�C; IR (ATR):2951, 1687, 1445, 1420, 1083, 831, 760 cm�1; 1H NMR (500MHz, DMSO-d6): d 0.00 (s, 9H), 0.88 (t, J ¼ 8.24 Hz, 2H),3.51 (td, J ¼ 9.08, 7.78 Hz, 1H), 3.66 (td, J ¼ 9.08, 8.09 Hz,

1H), 5.87–5.93 (m, 1H), 5.93–6.00 (m, 1H), 7.53–7.63 (m,




2H), 7.63–7.66 (m, 2H), 7.75 (dd, J ¼ 7.78, 1.37 Hz, 1H),7.86–7.95 (m, 2H), 7.97 (dd, J ¼ 7.63, 1.53 Hz, 1H), 10.04ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d �1.14,17.58, 66.23, 73.80, 128.82, 129.61, 129.64, 129.97, 131.09,131.11, 132.78, 134.31, 134.58, 136.05, 136.52, 136.70,

143.11, 143.79, 182.87 ppm; HRMS: m/z calcd. forC22H25N2O2SiS: 409.1406 [MþH]þ, found 409.1398.

11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazole-2-carbaldehyde (7g). Obtainedfrom 5a as a yellowish solid: Yield 78%; mp 94.58�C; IR

(ATR): 2952, 1684, 1449, 1215, 1073, 824, 772 cm�1; 1HNMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.94–0.99 (m,2H), 3.74–3.80 (m, 2H), 5.90 (s, 2H), 7.37–7.42 (m, 1H),7.49–7.54 (m, 2H), 7.61–7.68 (m, 2H), 7.87 (ddd, J ¼ 7.48,1.22, 1.07 Hz, 1H), 8.08 (d, J ¼ 2.44 Hz, 1H), 9.96 ppm (s,

1H); 13C NMR (126 MHz, DMSO-d6): d �1.03, 17.76, 66.45,73.50, 121.70, 123.34, 124.78, 126.22, 126.50, 127.44, 127.77,130.49, 130.97, 131.49, 131.90, 140.12, 144.81, 156.01,156.74, 182.96 ppm; HRMS: m/z calcd. for C22H24N2O3SiCl:

427.1245 [MþH]þ, found 427.1228.11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-

zo[2,3:6,7]thiepino[4,5-d]imidazole-2-carbaldehyde (7h). Obtainedfrom 5b as an amorphous yellowish solid: Yield 78%; IR(ATR): 2951, 1690, 1248, 1081, 832, 762 cm�1; 1H NMR

(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.89–0.93 (m, 2H),3.55–3.64 (m, 1H), 3.64–3.72 (m, 1H), 5.75 (d, J ¼ 10.68 Hz,1H), 5.99 (d, J ¼ 10.68 Hz, 1H), 7.52–7.61 (m, 2H), 7.66–7.73 (m, 2H), 7.85 (d, J ¼ 8.54 Hz, 1H), 7.94 (dd, J ¼ 7.78,1.37 Hz, 1H), 8.04 (d, J ¼ 2.44 Hz, 1H), 10.02 ppm (s, 1H);13C NMR (126 MHz, DMSO-d6): d �1.09, 17.71, 66.21,73.79, 128.93, 129.26, 129.84, 130.20, 130.74, 132.83, 132.88,134.10, 134.45, 134.63, 135.05, 135.77, 136.53, 143.53,143.88, 183.02 ppm; HRMS: m/z calcd. for C22H24N2O2SiSCl:443.1016 [MþH]þ, found 443.1005.

5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazole-2-carbaldehyde (7i). Obtainedfrom 6a as a yellowish solid: Yield 83%; mp 113.81�C; IR(ATR): 2946, 1688, 1238, 1211, 1083, 825, 773 cm�1; 1H

NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.92–0.99 (m,2H), 3.72–3.79 (m, 2H), 5.92 (s, 2H), 7.43–7.49 (m, 1H),7.54–7.59 (m, 2H), 7.59–7.67 (m, 2H), 7.83 (dd, J ¼ 2.29,0.76 Hz, 1H), 8.01–8.05 (m, 1H), 9.96 ppm (s, 1H); 13C NMR(126 MHz, DMSO-d6): d –1.08, 17.71, 66.51, 73.70, 121.23,

123.07, 123.70, 126.51, 126.63, 128.32, 128.55, 130.29,130.33, 132.26, 133.73, 138.24, 144.82, 155.53, 157.19,182.77 ppm; HRMS: m/z calcd. for C22H24N2O3ClSi:427.1245 [MþH]þ, found 427.1229.

5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]thiepino[4,5-d]imidazole-2-carbaldehyde (7j). Obtainedfrom 6b as an amorphous yellowish solid: Yield 62%; IR(ATR): 2950, 1688, 1434, 1247, 1084, 833, 767 cm�1; 1HNMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.85–0.91 (m,2H), 3.52 (td, J ¼ 9.00, 7.63 Hz, 1H), 3.66 (td, J ¼ 9.16, 7.93

Hz, 1H), 5.88–5.93 (m, 1H), 5.93–5.99 (m, 1H), 7.61 (dd, J ¼8.24, 2.44 Hz, 1H), 7.64–7.69 (m, 2H), 7.76 (d, J ¼ 8.54 Hz,1H), 7.87–7.97 (m, 3H), 10.05 ppm (s, 1H); 13C NMR (126MHz, DMSO-d6): d �1.14, 17.58, 66.29, 73.91, 128.09,

129.65, 129.87, 130.07, 130.94, 131.34, 133.31, 134.36,134.40, 134.44, 135.38, 136.93, 138.44, 141.74, 143.94,182.88 ppm; HRMS: m/z calcd. for C22H24N2O2SiSCl:443.1016 [MþH]þ, found 443.1002.

General procedure for reduction of aldehydes 7 (prepa-

ration of compounds 8). To a solution of 7 (0.34 g, 1.23mmol) in mixture of methanol (15 mL) and dichloromethane

(45 mL) sodium borohydride (0.074 g, 1.97 mmol) was addedportionwise. The reaction mixture was stirred for 2 h at roomtemperature, pH adjusted to 5–6, concentrated, diluted withwater (50 mL), and extracted with dichloromethane (3 � 30mL). The organic extract was washed with saturated sodium

hydrogencarbonate (50 mL), dried over anhydrous sodium sul-fate and evaporated to give compound 8.

(1-Methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl)me-thanol (8a). Obtained from 7a as a white solid: Yield 97%;mp 237.31�C; IR (ATR): 3184, 2923, 1515, 1196, 1024, 742

cm�1; 1H NMR (500 MHz, DMSO-d6): d 3.88 (s, 3H), 4.67(d, J ¼ 5.80 Hz, 2H), 5.52 (t, J ¼ 5.65 Hz, 1H), 7.22–7.27(m, 1H), 7.29–7.38 (m, 3H), 7.42 (td, J ¼ 7.63, 1.53 Hz,1H), 7.45–7.49 (m, 1H), 7.62 (dd, J ¼ 7.78, 1.68 Hz, 1H),7.72 ppm (dd, J ¼ 8.09, 1.68 Hz, 1H); 13C NMR (126

MHz, DMSO-d6): d 32.81, 56.46, 121.46, 122.65, 123.41,125.76, 125.88, 126.59, 126.72, 127.95, 128.09, 129.10,129.61, 135.65, 150.62, 155.84, 156.01 ppm; HRMS: m/zcalcd. for C17H14N2O2Na: 301.0953 [MþNa]þ, found

301.0957.(1-Methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl)me-

thanol (8b). Obtained from 7b as a white solid: Yield 77%;mp 182.69�C; IR (ATR): 3179, 2957, 2919, 1451, 1375, 1031,1018, 759, 741, 719 cm�1; 1H NMR (500 MHz, DMSO-d6): d3.81 (s, 3H), 4.66–4.74 (m, 2H), 5.55 (t, J ¼ 5.65 Hz, 1H),7.31–7.38 (m, 1H), 7.38–7.51 (m, 3H), 7.54–7.60 (m, 2H),7.70 (dd, J ¼ 7.78, 1.07 Hz, 1H), 7.78 ppm (dd, J ¼ 7.63,1.53 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d 32.73,56.57, 128.10, 128.45, 128.70, 129.12, 129.17, 129.26, 131.67,

132.51, 132.71, 133.22, 133.90, 134.08, 138.25, 139.56,149.69 ppm; HRMS: m/z calcd. for C17H14N2OSNa: 317.0725[MþNa]þ, found 317.0716.

[1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imi-dazol-2-yl]methanol (8c). Obtained from 7c as a white solid:

Yield 98%; mp 169.09�C; IR (ATR): 3119, 3059, 3030, 1513,1451, 1207, 1029, 763, 738, 696 cm�1; 1H NMR (500 MHz,DMSO-d6): d 2.94 (t, J ¼ 7.48 Hz, 2H), 4.49 (d, J ¼ 5.49 Hz,2H), 4.60 (t, J ¼ 7.63 Hz, 2H), 5.57–5.60 (m, 1H), 7.08–7.11(m, 2H), 7.17–7.27 (m, 4H), 7.32–7.39 (m, 3H), 7.41–7.50 (m,

2H), 7.68–7.76 ppm (m, 2H); 13C NMR (126 MHz, DMSO-d6): d 36.26, 46.43, 56.56, 121.39, 122.72, 123.69, 125.75,126.01, 126.07, 126.78, 126.98, 128.07, 128.81, 128.95,129.23, 129.72, 136.50, 138.12, 150.84, 156.00, 156.35 ppm;

HRMS: m/z calcd. for C24H20N2O2Na: 391.1422 [MþNa]þ,found 391.1423.

[1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imi-dazol-2-yl]methanol (8d). Obtained from 7d as a white solid:Yield 97%; mp 188.04�C; IR (ATR): 3162, 1454, 1418, 1036,

754, 715, 692 cm�1; 1H NMR (500 MHz, DMSO-d6): d 2.68–2.83 (m, 2H), 4.29 (d, J ¼ 13.12 Hz, 1H), 4.42–4.54 (m, 2H),4.62–4.71 (m, 1H), 5.59 (br. s., 1H), 6.97–7.03 (m, 2H), 7.13–7.23 (m, 3H), 7.32–7.53 (m, 4H), 7.58 (dd, J ¼ 7.78, 1.37 Hz,1H), 7.66–7.78 ppm (m, J ¼ 16.25, 16.25, 7.63, 1.37 Hz, 3H);13C NMR (126 MHz, DMSO-d6): d 36.24, 46.31, 56.46,126.89, 127.80, 128.21, 128.75, 128.97, 129.12, 129.30,129.37, 130.79, 132.50, 133.03, 133.91, 134.62, 138.08,138.21, 140.51, 149.91 ppm; HRMS: m/z calcd. forC24H21N2OS: 385.1375 [MþH]þ, found 385.1375.



[1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]ox-epino[4,5-d]imidazol-2-yl]methanol (8e). Obtained from 7e as awhite solid: Yield 99%; mp 147.68�C; IR (ATR): 3189, 2951,

2893, 1450, 1210, 1080, 835, 765, 743 cm�1; 1H NMR (500MHz, DMSO-d6): d 0.00 (s, 9H), 0.92–0.98 (m, 2H), 3.67–3.73 (m, 2H), 4.76 (d, J ¼ 5.80 Hz, 2H), 5.63 (s, 2H), 5.69 (t,J ¼ 5.80 Hz, 1H), 7.28–7.37 (m, 2H), 7.38–7.44 (m, 2H),7.45–7.54 (m, 2H), 7.75–7.81 (m, 1H), 7.84 ppm (dd, J ¼7.93, 1.53 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d�1.06, 17.68, 56.48, 65.96, 73.15, 121.47, 122.65, 123.30,125.80, 125.98, 126.82, 127.10, 127.78, 128.06, 129.45,130.00, 136.08, 151.14, 156.21 ppm; HRMS: m/z calcd. forC22H26N2O3SiNa: 417.1610 [MþNa]þ, found 417.1591.

[1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]-thiepino[4,5-d]imidazol-2-yl]methanol (8f). Obtained from 7f

as a white amorphous solid: Yield 98%; IR (ATR): 3195,3051, 2952, 1487, 1249, 1082, 1033, 858, 835, 760, 740 cm�1;1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.84–0.91 (m,

2H), 3.40–3.47 (m, 1H), 3.59–3.66 (m, 1H), 4.78–4.86 (m,2H), 5.58–5.65 (m, 1H), 5.65–5.72 (m, 1H), 5.75 (t, J ¼ 5.65Hz, 1H), 7.43–7.48 (m, 1H), 7.50–7.60 (m, 3H), 7.67 (dd, J ¼7.63, 1.22 Hz, 1H), 7.74 (dd, J ¼ 7.48, 1.68 Hz, 1H), 7.80

(dd, J ¼ 7.63, 1.53 Hz, 1H), 7.88 ppm (dd, J ¼ 7.63, 1.53 Hz,1H); 13C NMR (126 MHz, DMSO-d6): d �1.12, 17.58, 56.58,65.75, 73.13, 128.32, 128.75, 129.01, 129.20, 129.32, 129.60,131.90, 132.54, 132.69, 133.58, 133.90, 134.58, 137.86,139.89, 150.40 ppm; HRMS: m/z calcd. for C22H27N2O2SSi:

411.1563 [MþH]þ, found 411.1548.[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-

zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methanol (8g). Obtainedfrom 7g as a white amorphous solid: Yield 100%; IR (ATR):3179, 2951, 1491, 1446, 1248, 1211, 1076, 1031, 828, 773,

741 cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H),0.93–1.02 (m, 2H), 3.69–3.77 (m, 2H), 4.73 (d, J ¼ 5.80 Hz,2H), 5.58 (s, 2H), 5.69 (t, J ¼ 5.65 Hz, 1H), 7.26–7.34 (m,1H), 7.37–7.44 (m, 2H), 7.47–7.55 (m, 2H), 7.72–7.78 (m,1H), 7.91 ppm (d, J ¼ 2.44 Hz, 1H); 13C NMR (126 MHz,

DMSO-d6): d �1.02, 17.80, 56.36, 65.93, 73.08, 121.47,124.35, 125.08, 126.08, 126.42, 126.81, 126.94, 127.43,129.51, 129.79, 130.19, 136.90, 151.50, 154.65, 155.95 ppm;HRMS: m/z calcd. for C22H26ClN2O3Si: 429.1401 [MþH]þ,found 429.1398.

[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methanol (8h). Obtainedfrom 7h as a white amorphous solid: Yield 99%; IR (ATR):3191, 3070, 2952, 2923, 2889, 1581, 1480, 1366, 1249, 1078,

1030, 858, 835, 769, 736 cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.90–0.97 (m, 2H), 3.53 (td, J ¼ 9.00,7.93 Hz, 1H), 3.60–3.72 (m, 1H), 4.77 (d, J ¼ 5.80 Hz, 2H),5.44 (d, J ¼ 10.99 Hz, 1H), 5.66 (d, J ¼ 10.99 Hz, 1H), 5.72(t, J ¼ 5.65 Hz, 1H), 7.41–7.52 (m, 2H), 7.55 (dd, J ¼ 8.39,

2.29 Hz, 1H), 7.63 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.75 (d, J ¼8.24 Hz, 1H), 7.81–7.87 ppm (m, 2H); 13C NMR (126 MHz,DMSO-d6): d �1.07, 17.79, 56.42, 65.72, 73.11, 127.97,128.46, 129.28, 129.32, 129.42, 130.50, 132.58, 133.09,134.19, 134.43, 135.37, 137.65, 140.63, 150.67 ppm; HRMS:

m/z calcd. for C22H26ClN2O2SSi: 445.1173 [MþH]þ, found445.1157.

[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methanol (8i). Obtainedfrom 7i as a white amorphous solid: Yield 93%; IR (ATR):

3203, 3066, 2953, 2895, 1496, 1446, 1249, 1216, 10991, 1081,856, 835, 771, 742 cm�1; 1H NMR (500 MHz, DMSO-d6): d0.00 (s, 9H), 0.91–0.98 (m, 2H), 3.67–3.73 (m, 2H), 4.76 (d, J¼ 5.80 Hz, 2H), 5.64 (s, 2H), 5.72 (t, J ¼ 5.80 Hz, 1H), 7.35–7.41 (m, 1H), 7.44–7.56 (m, 4H), 7.71 (dd, J ¼ 1.98, 0.76 Hz,

1H), 7.86 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C NMR (126MHz, DMSO-d6): d �1.07, 17.67, 56.45, 66.03, 73.24, 122.69,122.94, 123.42, 125.93, 126.30, 127.23, 128.76, 129.00,129.59, 129.91, 130.34, 134.79, 151.49, 154.69, 155.87 ppm;HRMS: m/z calcd. for C22H26ClN2O3Si: 429.1401 [MþH]þ,found 429.1395.

[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methanol (8j). Obtainedfrom 7j as a white amorphous solid: Yield 99%; IR (ATR):3184, 3059, 2951, 1582, 1483, 1247, 1080, 1036, 834, 766,

749 cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H),0.82–0.93 (m, 2H), 3.43–3.54 (m, 1H), 3.54–3.66 (m, 1H),4.82 (dd, J ¼ 5.65, 2.29 Hz, 2H), 5.59–5.66 (m, 1H), 5.66–5.74 (m, 1H), 5.77 (t, J ¼ 5.65 Hz, 1H), 7.52 (dd, J ¼ 8.24,

2.44 Hz, 1H), 7.54–7.62 (m, 2H), 7.69 (d, J ¼ 8.24 Hz, 1H),7.75–7.82 (m, 2H), 7.83 ppm (d, J ¼ 2.44 Hz, 1H); 13C NMR(126 MHz, DMSO-d6): d �1.13, 17.57, 56.53, 65.82, 73.23,127.52, 128.68, 128.87, 129.61, 129.94, 132.26, 132.46,132.58, 133.90, 133.95, 134.03, 134.17, 138.65, 139.60,

150.75 ppm; HRMS: m/z calcd. for C22H26ClN2O2SSi:445.1173 [MþH]þ, found 445.1164.

General procedure for preparation of compounds 9. To a40% aq sodium hydroxide (1.66 mL) solution of 8 (60 mg,0.216 mmol) in toluene (2.8 mL), appropriate x-chloroalkyl-dimethylamine (0.862 mmol), and a catalytic amount of ben-zyltriethylammonium chloride were added. Reaction mixturewas heated at reflux until TLC indicated the reaction was com-plete, and then cooled to room temperature, diluted with water(30 mL), and extracted with ethyl acetate (3 � 15 mL). The

organic extract was washed with brine (30 mL), dried over an-hydrous sodium sulfate, and evaporated. After purification onsilica gel SPE cartridge using step gradient system for elutionn-hexane/(ethyl acetate/n-hexane/diethylamine 10:10:1.5) com-

pound 9 was isolated.Dimethyl(2-{[(1-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imi-

dazol-2-yl)methyl]oxy}ethyl)amine (9a). Obtained from 8a as ayellowish amorphous solid: Yield 59%; IR (ATR): 3059, 2939,2859, 2820, 2770, 1516, 1496, 1456, 1444, 1207, 1106, 1090,

1029, 762, 742 cm�1; 1H NMR (500 MHz, DMSO-d6): d 2.15(s, 6H), 2.45 (t, J ¼ 5.95 Hz, 2H), 3.61 (t, J ¼ 5.95 Hz, 2H),3.87 (s, 3H), 4.69 (s, 2H), 7.22–7.28 (m, 1H), 7.30–7.39 (m,3H), 7.41–7.50 (m, 2H), 7.63 (dd, J ¼ 7.78, 1.68 Hz, 1H),7.70–7.75 ppm (m, 1H); 13C NMR (126 MHz, DMSO-d6): d32.77, 45.86, 58.61, 64.80, 68.31, 121.48, 122.67, 123.22,125.81, 125.91, 126.67, 126.86, 127.89, 128.30, 129.26,129.80, 135.88, 147.59, 155.92, 156.06 ppm; HRMS: m/zcalcd. for C21H24N3O2: 350.1869 [MþH]þ, found 350.1854.

Dimethyl(3-{[(1-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imi-dazol-2-yl)methyl]oxy}propyl)amine (9b). Obtained from 8a as ayellowish amorphous solid: Yield 80%; IR (ATR): 3062, 2944,2859, 2817, 2768, 1517, 1497, 1458, 1444, 1207, 1089, 798,763, 743 cm�1; 1H NMR (500 MHz, DMSO-d6): d 1.68 (quin, J¼ 6.79 Hz, 2H), 2.10 (s, 6H), 2.26 (t, J ¼ 7.17 Hz, 2H), 3.55 (t,J ¼ 6.41 Hz, 2H), 3.87 (s, 3H), 4.66 (s, 2H), 7.22–7.28 (m, 1H),7.30–7.50 (m, 5H), 7.64 (dd, J ¼ 7.93, 1.53 Hz, 1H), 7.68–7.75ppm (m, 1H); 13C NMR (126 MHz, DMSO-d6): d 27.65, 32.75,




45.54, 56.30, 64.85, 68.58, 121.48, 122.66, 123.22, 125.80,125.91, 126.67, 126.88, 127.88, 128.30, 129.26, 129.80, 135.87,147.64, 155.93, 156.06 ppm; HRMS: m/z calcd. forC22H26N3O2: 364.2025 [MþH]þ, found 364.2014.

Dimethyl(2-{[(1-methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imi-dazol-2-yl)methyl]oxy}ethyl)amine (9c). Obtained from 8b as ayellowish amorphous solid: Yield 62%; IR (ATR): 3051, 2940,2859, 2819, 2770, 1487, 1452, 1103, 1031, 759, 741 cm�1; 1HNMR (500 MHz, DMSO-d6): d 2.16 (s, 6H), 2.46 (t, J ¼ 5.80Hz, 2H), 3.58–3.69 (m, 2H), 3.79 (d, J ¼ 0.92 Hz, 3H), 4.68–

4.75 (m, 2H), 7.32–7.52 (m, 4H), 7.55–7.61 (m, 2H), 7.69–7.74(m, 1H), 7.74–7.81 ppm (m, 1H); 13C NMR (126 MHz, DMSO-d6): d 32.69, 45.88, 58.65, 64.96, 68.40, 128.19, 128.57, 128.79,129.15, 129.20, 129.39, 131.96, 132.52, 132.55, 133.34, 133.93,134.22, 138.10, 139.79, 146.71 ppm; HRMS: m/z calcd. for

C21H24N3OS: 366.1640 [MþH]þ, found 366.1628.Dimethyl(3-{[(1-methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imi-

dazol-2-yl)methyl]oxy}propyl)amine (9d). Obtained from 8b as ayellowish amorphous solid: Yield 80%; IR (ATR): 3051, 2943,

2857, 2816, 2766, 1487, 1453, 1092, 1030, 759, 741 cm�1; 1HNMR (500 MHz, DMSO-d6): d 1.70 (quin, J ¼ 6.82 Hz, 2H),2.11 (s, 6 H), 2.27 (t, J ¼ 7.32 Hz, 2H), 3.53–3.62 (m, 2H), 3.79(s, 3H), 4.65–4.72 (m, 2H), 7.32–7.52 (m, 4H), 7.59 (ddd, J ¼10.83, 7.63, 1.37 Hz, 2H), 7.71 (dd, J ¼ 7.63, 1.53 Hz, 1H), 7.78

ppm (dd, J ¼ 7.63, 1.53 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d 27.68, 32.69, 45.57, 56.32, 65.01, 68.70, 128.18, 128.59,128.80, 129.14, 129.19, 129.39, 131.96, 132.52, 132.55, 133.33,133.92, 134.20, 138.09, 139.76, 146.76 ppm; HRMS: m/z calcd.for C22H25N3OSNa: 402.1616 [MþNa]þ, found 402.1610.

Dimethyl[2-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]amine (9e). Obtained from 8c

as a yellowish amorphous solid: Yield 72%; IR (ATR): 3062,3025, 2939, 2860, 2819, 2769, 1513, 1495, 1450, 1207, 1095,1037, 760, 743, 699 cm�1; 1H NMR (500 MHz, DMSO-d6): d2.15 (s, 6H), 2.45 (t, J ¼ 5.80 Hz, 2H), 2.94 (t, J ¼ 7.63 Hz,2H), 3.59 (t, J ¼ 5.80 Hz, 2H), 4.53 (s, 2H), 4.57 (t, J ¼ 7.48Hz, 2H), 7.08–7.13 (m, 2H), 7.17–7.28 (m, 4H), 7.32–7.40 (m,3H), 7.42–7.50 (m, 2H), 7.69–7.77 ppm (m, 2H); 13C NMR

(126 MHz, DMSO-d6): d 36.20, 45.87, 46.44, 58.67, 64.82,68.27, 121.40, 122.75, 123.49, 125.79, 126.09, 126.16, 126.86,127.01, 127.34, 127.87, 128.84, 128.94, 129.38, 129.91,136.73, 138.02, 147.68, 156.11, 156.41 ppm; HRMS: m/zcalcd. for C28H30N3O2: 440.2338 [MþH]þ, found 440.2325.

Dimethyl[3-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine (9f). Obtained from 8c

as a yellowish amorphous solid: Yield 52%; IR (ATR): 3059,3025, 2942, 2859, 2816, 2766, 1513, 1495, 1450, 1207, 1092,761, 743, 699 cm�1; 1H NMR (500 MHz, DMSO-d6): d 1.68

(quin, J ¼ 6.72 Hz, 2H), 2.07 (s, 6H), 2.25 (t, J ¼ 7.17 Hz,2H), 2.94 (t, J ¼ 7.63 Hz, 2H), 3.53 (t, J ¼ 6.41 Hz, 2H),4.50 (s, 2H), 4.57 (t, J ¼ 7.48 Hz, 2H), 7.08–7.12 (m, 2H),7.18–7.28 (m, 4H), 7.32–7.40 (m, 3H), 7.42–7.50 (m, 2H),7.69–7.76 ppm (m, 2H); 13C NMR (126 MHz, DMSO-d6): d27.69, 36.23, 45.51, 46.43, 56.34, 64.90, 68.69, 121.40,122.75, 123.48, 125.78, 126.08, 126.17, 126.86, 127.04,127.36, 127.86, 128.85, 128.91, 129.38, 129.91, 136.70,137.98, 147.70, 156.12, 156.41 ppm; HRMS: m/z calcd. for

C29H32N3O2: 454.2495 [MþH]þ, found 454.2498.Dimethyl[2-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-

d]imidazol-2-yl]methyl}oxy)ethyl]amine (9g). Obtained from 8d

as a yellowish amorphous solid: Yield 44%; IR (ATR): 3055,

2939, 2859, 2818, 2768, 1485, 1454, 1422, 1109, 1057, 1032,758, 741, 698 cm�1; 1H NMR (500 MHz, DMSO-d6): d 2.15 (s,6H), 2.45 (t, J ¼ 5.80 Hz, 2H), 2.68–2.83 (m, 2H), 3.53–3.64(m, 2H), 4.34 (d, J ¼ 12.51 Hz, 1H), 4.37–4.46 (m, 1H), 4.54 (d,J ¼ 12.21 Hz, 1H), 4.66 (ddd, J ¼ 14.19, 8.24, 5.34 Hz, 1H),

6.98–7.03 (m, 2H), 7.14–7.23 (m, 3H), 7.33–7.53 (m, 4H), 7.59(dd, J ¼ 7.78, 1.37 Hz, 1H), 7.67–7.78 ppm (m, 3H); 13C NMR(126 MHz, DMSO-d6): d 36.17, 45.88, 46.33, 58.68, 64.84,68.30, 126.92, 127.93, 128.30, 128.77, 128.84, 128.96, 129.15,129.39, 129.42, 131.10, 132.51, 132.86, 133.93, 134.03, 134.80,

138.00, 138.05, 140.73, 146.74 ppm; HRMS: m/z calcd. forC28H30N3OS: 456.2110 [MþH]þ, found 456.2095.

Dimethyl[3-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]thie-pino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine (9h). Obtainedfrom 8d as a yellowish amorphous solid: Yield 65%; IR (ATR):

3055, 3025, 2941, 2857, 2815, 2765, 1485, 1455, 1432, 1089,1078, 758, 741, 698 cm�1; 1H NMR (500 MHz, DMSO-d6): d 1.68(quin, J ¼ 6.79 Hz, 2H), 2.09 (s, 6H), 2.21–2.32 (m, 2H), 2.68–2.84 (m, 2H), 3.46–3.59 (m, 2H), 4.29 (d, J ¼ 12.51 Hz, 1H), 4.39

(ddd, J ¼ 14.88, 7.78, 7.55 Hz, 1H), 4.53 (d, J ¼ 12.21 Hz, 1H),4.62–4.71 (m, 1H), 6.98–7.02 (m, 2H), 7.14–7.22 (m, 3H), 7.33–7.38 (m, 1H), 7.40–7.47 (m, 2H), 7.50 (td, J ¼ 7.55, 1.37 Hz, 1H),7.59 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.67–7.77 ppm (m, 3H); 13CNMR (126 MHz, DMSO-d6): d 27.67, 36.21, 45.52, 46.33, 56.34,

64.92, 68.74, 126.94, 127.94, 128.30, 128.79, 128.85, 128.93,129.14, 129.37, 129.42, 131.12, 132.51, 132.84, 133.93, 134.03,134.79, 137.96, 138.02, 140.69, 146.78 ppm; HRMS: m/z calcd. forC29H32N3OS: 470.2266 [MþH]þ, found 470.2253.

Dimethyl[2-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]amine(9i). Obtained from 8e as a yellowish amorphous solid: Yield74%; IR (ATR): 2949, 2893, 2851, 2819, 2769, 1450, 1248,1210, 1077, 856, 834, 763, 743 cm�1; 1H NMR (500 MHz,DMSO-d6): d �0.01 (br. s., 9H), 0.94 (t, J ¼ 7.93 Hz, 2H),

2.20 (s, 6H), 2.49 (t, J ¼ 5.95 Hz, 2H), 3.63–3.73 (m, 4H),4.77 (s, 2H), 5.59 (s, 2H), 7.27–7.38 (m, 2H), 7.38–7.45 (m,2H), 7.45–7.55 (m, 2H), 7.73–7.80 (m, 1H), 7.81–7.88 ppm(m, 1H); 13C NMR (126 MHz, DMSO-d6): d �1.04, 17.74,

45.90, 58.62, 64.74, 65.99, 68.42, 73.32, 121.48, 122.68,122.71, 123.15, 125.85, 126.02, 126.90, 127.20, 127.62,128.37, 129.59, 130.17, 136.32, 147.98, 156.27 ppm; HRMS:m/z calcd. for C26H36N3O3Si: 466.2526 [MþH]þ, found466.2529.

Dimethyl[3-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine(9j). Obtained from 8e as a yellowish amorphous solid: Yield83%; IR (ATR): 2949, 2855, 2815, 2765, 1450, 1210, 1075,857, 833, 764, 743 cm�1; 1H NMR (500 MHz, DMSO-d6): d0.00 (s, 9H), 0.91–0.99 (m, 2H), 1.72 (quin, J ¼ 6.82 Hz, 2H),2.14 (s, 6H), 2.29 (t, J ¼ 7.17 Hz, 2H), 3.60 (t, J ¼ 6.41 Hz,2H), 3.66–3.73 (m, 2H), 4.73 (s, 2H), 5.58 (s, 2H), 7.27–7.38(m, 2H), 7.38–7.44 (m, 2H), 7.45–7.54 (m, 2H), 7.74–7.79 (m,1H), 7.84 ppm (dd, J ¼ 7.93, 1.22 Hz, 1H); 13C NMR (126

MHz, DMSO-d6): d �1.07, 17.74, 27.66, 45.55, 56.31, 64.84,66.02, 68.80, 73.30, 121.48, 122.68, 123.15, 125.83, 126.01,126.90, 127.19, 127.62, 128.39, 129.58, 130.17, 136.29,148.01, 156.27 ppm; HRMS: m/z calcd. for C27H38N3O3Si:

480.2682 [MþH]þ, found 480.2692.Dimethyl[2-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-

zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]amine(9k). Obtained from 8f as a yellowish amorphous solid: Yield



61%; IR (ATR): 2949, 2897, 2863, 2818, 2768, 1485, 1461,1365, 1248, 1077, 1037, 833, 759 cm�1; 1H NMR (500 MHz,DMSO-d6): d 0.00 (s, 9H), 0.84–0.91 (m, 2H), 2.25 (s, 6H),2.55 (t, J ¼ 5.95 Hz, 2H), 3.38–3.48 (m, 1H), 3.58–3.66 (m,1H), 3.69–3.78 (m, 2H), 4.78–4.87 (m, 2H), 5.55 (d, J ¼10.99 Hz, 1H), 5.67 (d, J ¼ 10.99 Hz, 1H), 7.42–7.48 (m,1H), 7.49–7.59 (m, 3H), 7.67 (d, J ¼ 7.63 Hz, 1H), 7.73–7.82(m, 2H), 7.87 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C NMR(126 MHz, DMSO-d6): d �1.12, 17.63, 45.91, 58.64, 64.88,65.77, 68.55, 73.31, 128.39, 128.83, 129.09, 129.22, 129.34,

129.71, 132.14, 132.54, 132.56, 133.71, 133.93, 134.67,137.72, 140.13, 147.25 ppm; HRMS: m/z calcd. forC26H36N3O2SSi: 482.2298 [MþH]þ, found 482.2314.

Dimethyl[3-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine(9l). Obtained from 8f as a yellowish amorphous solid: Yield82%; IR (ATR): 2949, 2859, 2815, 2764, 1485, 1461, 1248,1076, 833, 759, 694 cm�1; 1H NMR (500 MHz, DMSO-d6): d0.00 (s, 9H), 1.78 (quin, J ¼ 6.79 Hz, 2H), 2.19 (s, 6H), 2.31–

2.40 (m, 2H), 3.37–3.49 (m, 1H), 3.58–3.71 (m, 3H), 4.74–4.84 (m, 2H), 5.53 (d, J ¼ 11.29 Hz, 1H), 5.66 (d, J ¼ 11.29Hz, 1H), 7.42–7.49 (m, 1H), 7.49–7.60 (m, 3H), 7.67 (dd, J ¼7.63, 1.22 Hz, 1H), 7.78 (ddd, J ¼ 18.16, 7.48, 1.53 Hz, 2H),7.87 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C NMR (126 MHz,

DMSO-d6): d �1.14, 17.64, 27.68, 45.57, 56.32, 64.96, 65.80,68.92, 73.31, 128.40, 128.84, 129.09, 129.22, 129.33, 129.72,132.15, 132.54, 132.56, 133.70, 133.93, 134.66, 137.70,140.09, 147.30 ppm; HRMS: m/z calcd. for C27H38N3O2SSi:482.2298 [MþH]þ, found 482.2314.

[2-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]dime-thylamine (9m). Obtained from 8g as a yellowish amorphoussolid: Yield 72%; IR (ATR): 2949, 2893, 2859, 2819, 2769,1491, 1446, 1248, 1211, 1075, 830, 773, 742 cm�1; 1H NMR

(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.94–1.00 (m, 2H),2.19 (s, 6H), 2.48 (t, J ¼ 5.80 Hz, 2H), 3.65 (t, J ¼ 5.80 Hz,2H), 3.68–3.76 (m, 2H), 4.75 (s, 2H), 5.55 (s, 2H), 7.27–7.34(m, 1H), 7.41 (d, J ¼ 3.66 Hz, 2H), 7.49–7.55 (m, 2H), 7.75

(dd, J ¼ 7.02, 0.61 Hz, 1H), 7.92 ppm (d, J ¼ 2.14 Hz, 1H);13C NMR (126 MHz, DMSO-d6): d �1.02, 17.87, 45.83,58.55, 64.58, 65.93, 68.35, 73.24, 121.48, 124.38, 124.93,126.11, 126.52, 127.01, 127.14, 127.27, 129.68, 129.91,130.20, 137.12, 148.37, 154.71, 156.01 ppm; HRMS: m/zcalcd. for C26H35ClN3O3Si: 500.2136 [MþH]þ, found500.2136.

[3-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]di-methylamine (9n). Obtained from 8g as a yellowish amorphous

solid: Yield 85%; IR (ATR): 2950, 2860, 2816, 2765, 1492,

1446, 1249, 1212, 1074, 857, 831, 772, 742 cm�1; 1H NMR

(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.94–1.00 (m, 2H),

1.70 (quin, J ¼ 6.79 Hz, 2H), 2.12 (s, 6H), 2.27 (t, J ¼ 7.17

Hz, 2H), 3.57 (t, J ¼ 6.41 Hz, 2H), 3.68–3.75 (m, 2H), 4.71

(s, 2H), 5.53 (s, 2H), 7.28–7.33 (m, 1H), 7.41 (d, J ¼ 3.66 Hz,

2H), 7.49–7.55 (m, 2H), 7.74–7.77 (m, 1H), 7.92 ppm (d, J ¼2.14 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d �1.04,

17.86, 27.62, 45.52, 56.28, 64.69, 65.96, 68.81, 73.23, 121.49,

124.38, 124.92, 126.11, 126.50, 127.02, 127.15, 127.25,

129.68, 129.91, 130.20, 137.08, 148.43, 154.71, 156.01 ppm;

HRMS: m/z calcd. for C27H37ClN3O3Si: 514.2293 [MþH]þ,found 514.2288.

[2-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]di-methylamine (9o). Obtained from 8h as a yellowish amorphous

solid: Yield 62%; IR (ATR): 2949, 2893, 2863, 2863, 2768,1580, 1479, 1460, 1364, 1248, 1101, 1076, 1030, 833, 769,744 cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H),0.88–0.96 (m, 2H), 2.21 (s, 6H), 2.50 (t, J ¼ 5.80 Hz, 2H),3.52 (td, J ¼ 9.16, 7.93 Hz, 1H), 3.62–3.74 (m, 3H), 4.78 (s,

2H), 5.41 (d, J ¼ 10.99 Hz, 1H), 5.63 (d, J ¼ 10.68 Hz, 1H),7.41–7.53 (m, 2H), 7.56 (dd, J ¼ 8.39, 2.29 Hz, 1H), 7.63 (dd,J ¼ 7.63, 1.22 Hz, 1H), 7.76 (d, J ¼ 8.54 Hz, 1H), 7.83 (dd, J¼ 7.63, 1.53 Hz, 1H), 7.87 ppm (d, J ¼ 2.14 Hz, 1H); 13CNMR (126 MHz, DMSO-d6): d �1.07, 17.82, 45.90, 58.62,

64.68, 65.71, 68.55, 73.28, 128.07, 128.53, 129.41, 129.46,130.77, 132.59, 133.19, 133.23, 134.21, 134.30, 135.39,137.49, 140.83, 147.58 ppm; HRMS: m/z calcd. forC26H35ClN3O2SSi: 516.1908 [MþH]þ, found 516.1909.

[3-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)pro-pyl]dimethylamine (9p). Obtained from 8h as a yellowishamorphous solid: Yield 77%; IR (ATR): 2949, 2859, 2815,2765, 1581, 1461, 1365, 1248, 1075, 1029, 857, 833, 769, 744

cm�1; 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.89–0.98 (m, 2H), 1.74 (quin, J ¼ 6.79 Hz, 2H), 2.15 (s, 6H),2.26–2.37 (m, 2H), 3.47–3.56 (m, 1H), 3.58–3.72 (m, 3H),4.71–4.80 (m, 2H), 5.41 (d, J ¼ 10.99 Hz, 1H), 5.62 (d, J ¼10.99 Hz, 1H), 7.41–7.53 (m, 2H), 7.56 (dd, J ¼ 8.24, 2.14

Hz, 1H), 7.63 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.76 (d, J ¼ 8.24Hz, 1H), 7.83 (dd, J ¼ 7.63, 1.53 Hz, 1H), 7.87 ppm (d, J ¼2.44 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d �1.09,17.82, 27.66, 45.56, 56.30, 64.78, 65.74, 68.91, 73.29, 128.07,128.53, 129.41, 129.46, 130.79, 132.60, 133.19, 133.22,

134.21, 134.30, 135.39, 137.48, 137.50, 140.80, 147.64 ppm;HRMS: m/z calcd. for C27H37ClN3O2SSi: 530.2064 [MþH]þ,found 530.2061.

[2-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]dime-thylamine (9r). Obtained from 8i as a yellowish amorphoussolid: Yield 74%; IR (ATR): 2949, 2893, 2859, 2814, 2765,1495, 1445, 1213, 1098, 1075, 853, 828, 769, 745 cm�1; 1HNMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.91–0.98 (m, 2H),2.20 (s, 6H), 2.50 (t, J ¼ 5.80 Hz, 2H), 3.63–3.74 (m, 4H), 4.77

(s, 2H), 5.61 (s, 2H), 7.34–7.41 (m, 1H), 7.44–7.57 (m, 4H),7.70–7.73 (m, 1H), 7.87 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13CNMR (126 MHz, DMSO-d6): d �1.07, 17.72, 45.89, 58.61,64.67, 66.06, 68.45, 73.42, 122.72, 122.80, 123.43, 126.01,

126.32, 127.32, 129.07, 129.12, 129.43, 129.95, 130.49, 135.03,148.33, 154.76, 155.94 ppm; HRMS: m/z calcd. forC26H35ClN3O3Si: 500.2136 [MþH]þ, found 500.2135.

[3-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]dime-thylamine (9s). Obtained from 8i as a yellowish amorphoussolid: Yield 81%; IR (ATR): 2949, 2855, 2816, 2765, 1495,1478, 1445, 1247, 1213, 1074, 854, 828, 769 cm�1; 1H NMR(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.91–0.98 (m, 2H),1.73 (quin, J ¼ 6.82 Hz, 2H), 2.14 (s, 6 H), 2.30 (t, J ¼ 7.17

Hz, 2H), 3.60 (t, J ¼ 6.41 Hz, 2H), 3.67–3.73 (m, 2H), 4.74(s, 2H), 5.59 (s, 2H), 7.38 (ddd, J ¼ 7.78, 7.02, 1.37 Hz, 1H),7.44–7.57 (m, 4H), 7.71 (t, J ¼ 0.92 Hz, 1H), 7.86 ppm (dd, J¼ 7.78, 1.37 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d�1.08, 17.72, 27.65, 45.54, 56.30, 64.74, 66.09, 68.83, 73.40,




122.72, 122.79, 123.43, 126.01, 126.32, 127.32, 129.08,129.13, 129.42, 129.95, 130.51, 135.00, 148.38, 154.75,155.94 ppm; HRMS: m/z calcd. for C27H37ClN3O3Si:514.2293 [MþH]þ, found 514.2296.

[2-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]di-methylamine (9t). Obtained from 8j as a yellowish amorphoussolid: Yield 82%; IR (ATR): 2949, 2889, 2859, 2765, 1582,1482, 1456, 1248, 1078, 1038, 834, 765, 748 cm�1; 1H NMR(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.84–0.92 (m, 2H), 2.26

(s, 6H), 2.56 (t, J ¼ 5.80 Hz, 2H), 3.40–3.48 (m, 1H), 3.58–3.66(m, 1H), 3.69–3.78 (m, 2H), 4.78–4.88 (m, 2H), 5.57 (d, J ¼11.29 Hz, 1H), 5.68 (d, J ¼ 10.99 Hz, 1H), 7.50–7.62 (m, 3H),7.69 (d, J ¼ 8.24 Hz, 1H), 7.76–7.85 ppm (m, 3H); 13C NMR(126 MHz, DMSO-d6): d �1.14, 17.60, 45.89, 58.62, 64.80,

65.84, 68.58, 73.42, 127.59, 128.78, 128.96, 129.63, 130.05,132.33, 132.39, 132.81, 134.00, 134.02, 134.06, 134.19, 138.87,139.44, 147.62 ppm; HRMS: m/z calcd. for C26H35ClN3O2SSi:516.1908 [MþH]þ, found 516.1909.

[3-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)pro-pyl]dimethylamine (9v). Obtained from 8j as a yellowish oil:Yield 87%; IR (ATR): 2949, 2859, 2815, 2765, 1582, 1460,1248, 1077, 834, 766, 748 cm�1; 1H NMR (500 MHz, DMSO-

d6): d 0.00 (s, 9H), 0.85–0.92 (m, 2H), 1.79 (quin, J ¼ 6.82Hz, 2H), 2.20 (s, 6H), 2.37 (t, J ¼ 6.87 Hz, 2H), 3.57–3.73(m, 4H), 4.74–4.85 (m, 2H), 5.55 (d, J ¼ 11.29 Hz, 1H), 5.67(d, J ¼ 11.29 Hz, 1H), 7.50–7.62 (m, 3H), 7.69 (d, J ¼ 8.24Hz, 1H), 7.76–7.85 ppm (m, 3H); 13C NMR (126 MHz,

DMSO-d6): d �1.14, 17.61, 27.63, 40.37, 45.54, 56.30, 64.85,65.87, 68.93, 73.41, 127.59, 128.79, 128.97, 129.63, 130.07,132.32, 132.38, 132.81, 134.00, 134.06, 134.19, 138.84,139.43, 147.68 ppm; HRMS: m/z calcd. for C27H37ClN3O2SSi:530.2064 [MþH]þ, found 530.2048.

General procedure for preparation of compounds 10. Toa solution of 9 (61.6 mg, 0.132 mmol) in methanol (3.4 mL),0.5M hydrochloric acid in methanol (1.15 mL) was slowlyadded. The reaction mixture was heated for 2 h at 60�C, thencooled to room temperature, and concentrated. Ethyl acetate (4mL) and water were added (6 mL) and pH adjusted to 1.0 usinga 3M hydrochloric acid. The layers were separated and the aque-ous layer washed with diethyl ether (2 � 10 mL). The pH of theaqueous layer was adjusted to pH 9.5 with 5M sodium hydroxide

and extracted with ethyl acetate (3 � 10 mL). The combined or-ganic extracts were washed with brine (15 mL) and dried overanhydrous sodium sulfate. The drying agent was filtered off, andsolvent was removed in vacuo to give the crude product 10.

{2-[(1H-Dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-ylmethy-l)oxy]ethyl}dimethylamine (10a). Obtained from 9i as a yel-lowish amorphous solid: Yield 89%; IR (ATR): 3055, 2947,2858, 2826, 2772, 1501, 1454, 1341, 1216, 1098, 1035, 743cm�1; 1H NMR (500 MHz, DMSO-d6): d 2.17 (s, 6H), 2.48 (t,J ¼ 5.95 Hz, 2H), 3.63 (t, J ¼ 5.80 Hz, 2H), 4.60 (s, 2H),

7.21–7.30 (m, 2H), 7.30–7.37 (m, 4H), 7.64 (d, J ¼ 7.32 Hz,2H), 12.98 ppm (br. s., 1H); 13C NMR (126 MHz, DMSO-d6):d 45.83, 58.59, 65.67, 68.49, 122.01, 125.78, 126.05, 129.30,147.43, 154.61 ppm; HRMS: m/z calcd. for C20H22N3O2:

336.1712 [MþH]þ, found 336.1726.{3-[(1H-Dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-ylme-

thyl)oxy]propyl}dimethylamine (10b). Obtained from 9j as ayellowish amorphous solid: Yield 76%; IR (ATR): 3055, 2946,

2860, 2824, 2776, 1501, 1453, 1216, 1096, 1031, 760, 742 cm�1;1H NMR (500 MHz, DMSO-d6): d 1.69 (quin, J ¼ 6.82 Hz, 2H),2.11 (s, 6H), 2.27 (t, J ¼ 7.17 Hz, 2H), 3.55 (t, J ¼ 6.56 Hz, 2H),4.56 (s, 2H), 7.21–7.29 (m, 2H), 7.30–7.39 (m, 4H), 7.65 (d, J ¼6.10 Hz, 2H), 12.91 ppm (br. s., 1H); 13C NMR (126 MHz,

DMSO-d6): d 27.66, 45.51, 56.34, 65.61, 68.70, 122.00, 125.75,126.11, 129.31, 147.34, 154.62 ppm; HRMS: m/z calcd. forC21H24N3O2: 350.1869 [MþH]þ, found 350.1854.

{2-[(1H-Dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-ylmethy-l)oxy]ethyl}dimethylamine (10c). Obtained from 9k as a yel-

lowish amorphous solid: Yield 90%; IR (ATR): 3044, 2944,2855, 2824, 2772, 1489, 1459, 1340, 1115, 1032, 757 cm�1;1H NMR (500 MHz, DMSO-d6): d 2.18 (s, 6H), 2.49 (t, J ¼6.10 Hz, 2H), 3.66 (t, J ¼ 5.80 Hz, 2H), 4.62 (s, 2H), 7.32–7.47 (m, 4H), 7.58 (d, J ¼ 7.63 Hz, 2H), 7.67 (d, J ¼ 2.75

Hz, 2H), 13.02 ppm (br. s., 1H); 13C NMR (126 MHz,DMSO-d6): d 45.81, 58.60, 65.64, 68.60, 127.69, 129.09,129.20, 131.71, 132.87, 146.82 ppm; HRMS: m/z calcd. forC20H22N3OS: 352.1484 [MþH]þ, found 352.1477.

{3-[(1H-Dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-ylmethy-l)oxy]propyl}dimethylamine (10d). Obtained from 9l as a yel-lowish amorphous solid: Yield 86%; IR (ATR): 3051, 2944,2860, 2820, 2772, 1489, 1461, 1355, 1093, 1032, 757 cm�1;1H NMR (500 MHz, DMSO-d6): d 1.70 (quin, J ¼ 6.82 Hz,

2H), 2.11 (s, 6H), 2.29 (t, J ¼ 7.32 Hz, 2H), 3.57 (t, J ¼ 6.41Hz, 2H), 4.59 (s, 2H), 7.33–7.47 (m, 4H), 7.58 (d, J ¼ 7.63Hz, 2H), 7.67 (br. s., 2H), 12.90 ppm (br. s., 1H); 13C NMR(126 MHz, DMSO-d6): d 45.81, 58.60, 65.64, 68.60, 127.69,129.09, 129.20, 131.71, 132.87, 146.82 ppm; HRMS: m/zcalcd. for C21H24N3OS: 366.1640 [MþH]þ, found 366.1646.

(2-{[(11-Chloro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl)methyl]oxy}ethyl)dimethylamine (10e).. Obtained eitherfrom 9m (yield 90%) or 9r (yield 83%) as a yellowish amor-phous solid: IR (ATR): 3059, 2946, 2858, 2825, 2772, 1601,

1497, 1444, 1220, 1101, 836, 768, 742 cm�1; 1H NMR (500MHz, DMSO-d6): d 2.18 (s, 6H), 2.48 (t, J ¼ 5.95 Hz, 2H),3.63 (t, J ¼ 5.80 Hz, 2H), 4.60 (s, 2H), 7.25–7.32 (m, 1H),7.34–7.41 (m, 4H), 7.61–7.68 (m, 2H), 13.00 ppm (br. s., 1H);13C NMR (126 MHz, DMSO-d6): d 45.82, 58.58, 65.64, 68.54,122.09, 123.83, 125.28, 126.07, 126.14, 128.68, 129.71,129.84, 147.94, 153.09, 154.29 ppm; HRMS: m/z calcd. forC20H21N3O2Cl: 370.1322 [MþH]þ, found 370.1335.

(3-{[(11-Chloro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl)methyl]oxy}propyl)dimethylamine (10f). Obtained eitherfrom 9n (yield 89.0%) or 9s (yield 88.0%) as a yellowishamorphous solid: IR (ATR): 3055, 2946, 2861, 2823, 2776,1496, 1446, 1220, 1092, 835, 814, 767, 741 cm�1; 1H NMR(500 MHz, DMSO-d6): d 1.69 (quin, J ¼ 6.82 Hz, 2H), 2.11

(s, 6H), 2.28 (t, J ¼ 7.32 Hz, 2H), 3.55 (t, J ¼ 6.56 Hz, 2H),4.56 (s, 2H), 7.24–7.31 (m, 1H), 7.34–7.40 (m, 4H), 7.62–7.70(m, 2H), 12.96 ppm (br. s., 1H); 13C NMR (126 MHz, DMSO-d6): d 27.63, 45.50, 56.32, 65.57, 68.76, 122.08, 123.82,125.33, 126.04, 126.21, 128.69, 129.71, 129.83, 147.87,

153.09, 154.29 ppm; HRMS: m/z calcd. for C21H23N3O2Cl:384.1479 [MþH]þ, found 384.1471.

(2-{[(11-Chloro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl)methyl]oxy}ethyl)dimethylamine (10g). Obtained either

from 9o (yield 90%) or 9t (yield 91%) as a white amorphoussolid: IR (ATR): 3202, 2937, 2865, 2824, 2773, 1580, 1485,1456, 1353, 1093, 1030, 811, 766 cm�1; 1H NMR (500 MHz,DMSO-d6): d 2.18 (s, 6H), 2.50 (t, J ¼ 6.10 Hz, 2H), 3.66 (t,



J ¼ 5.80 Hz, 2H), 4.63 (s, 2H), 7.36–7.50 (m, 3H), 7.56–7.62(m, 2H), 7.63–7.72 (m, 2H), 13.07 ppm (br. s., 1H); 13C NMR(126 MHz, DMSO-d6): d 45.79, 58.57, 65.60, 68.64, 126.99,127.78, 128.61, 129.48, 130.29, 131.20, 133.03, 133.95,134.41, 147.33 ppm; HRMS: m/z calcd. for C20H21N3OSCl:

386.1094 [MþH]þ, found 386.1110.(3-{[(11-Chloro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-

2-yl)methyl]oxy}propyl)dimethylamine (10h). Obtained either

from 9p (yield 95%) or 9v (yield 91%) as a yellowish amor-

phous solid: IR (ATR): 2943, 2860, 2819, 2772, 1579, 1484,

1459, 1094, 1030, 810, 765 cm�1; 1H NMR (500 MHz,

DMSO-d6): d 1.70 (quin, J ¼ 6.82 Hz, 2H), 2.11 (s, 6H), 2.29

(t, J ¼ 7.32 Hz, 2H), 3.58 (t, J ¼ 6.56 Hz, 2H), 4.59 (s, 2H),

7.34–7.49 (m, 3H), 7.54–7.62 (m, 2H), 7.62–7.75 (m, 2H),

13.01 ppm (br. s., 1H); 13C NMR (126 MHz, DMSO-d6): d27.65, 45.52, 56.34, 65.51, 68.85, 127.05, 127.86, 128.62,

129.46, 129.50, 130.30, 131.22, 133.02, 133.94, 134.40,

147.21 ppm; HRMS: m/z calcd. for C21H23N3OSCl: 400.1250

[MþH]þ, found 400.1254.

Biology

Cell isolation. Peripheral blood mononuclear cells (PBMC)were obtained from buffy coat of healthy volunteer donors bya density gradient centrifugation. Buffy coat was mixed withone volume of sterile saline, sample layered over FicollPa-

queTM Plus (Amersham Biosciences), and centrifuged at 400� g for 30 min. PBMCs were collected, washed in RPMI1640 medium, and centrifuged. Finally, cells were resuspendedin RPMI 1640 containing 10% heat inactivated fetal bovine se-

rum (Biowest) and counted.Cell culture. PBMCs were cultured at a concentration of

3.5 � 104 in 200 lL volumes in 96-well cell culture plates

(Falcon, St. Albans, UK) at 37�C in humidified atmosphere

containing 5% CO2. The cells were either stimulated with

LPS (serotype 0111:B4, Sigma) at 1 ng/mL final concentra-

tion or left unstimulated (cultured in medium alone). Com-

pound stock solutions were prepared as 10 mM in DMSO.

Final 10 lM and 3 lM (10–0.03 lM) concentration made in

cell culture medium were tested when they had been added

together with LPS. The final DMSO volume ratio in all

assays did not exceed 0.1%. Negative and LPS control sam-

ples were prepared in sextaplicates and tested compound sam-

ples in triplicates.Cytokine measurement. Cell free supernatants were taken

after overnight period and quantified for TNF-a content by

enzyme linked immunosorbent assay (ELISA). To ensure the

detection specificity and sensitivity, assay was performed

according to manufacturer instructions (R&D Systems) using

suggested pair of antibodies specific for human TNF-a. Testsensitivity for measuring human TNF-a was under 5 pg/mL.

To calculate results, standard curve was made out of measured

OD values for recombinant TNF-a of known concentrations.

TNF-a content in unknown samples was calculated out of OD

values extrapolated from the standard curve. Inhibition values

were calculated according to formula:

X ¼ ConcðcompoundÞ � Concðmedium controlÞConcðLPS controlÞ � Conc ðmedium controlÞ � 100ð%Þ

IC50 values are calculated using GraphPad Prism

software.

Acknowledgment. The authors express gratitude to Josip Kles-cic for his assistance with the synthesis, Zeljko Osman and

Dubravka Gembarovski for the mass spectroscopy support, Stef-ica Flegar and Goran Landek for IR spectra, Biserka Metelko forthe NMR spectroscopy, and Vitomir Sunjic for helpfuldiscussions.

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